This project explores pharmacokinetic and pharmacodynamic approaches to developing new treatments for drug dependence and reduction of HIV transmission risk behaviors, with a current focus on cocaine and marijuana dependence. Many subjects are at high risk for contracting and spreading HIV infection. HIV transmission risk behaviors are assessed and HIV testing and risk reduction counseling are offered to all subjects. The pharmacokinetic approach being studied is blunting the rate of onset of drug effect by enhancement of drug metabolism. Rate of onset of drug effect is considered an important influence on the reinforcing effects of drugs, but this has never been systematically studied in humans with stimulants. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. Enhancement of cocaine metabolism is being studied using butyrylcholinesterase (BChE),a major cocaine-metabolizing enzyme in humans. Increased BChE activity might reduce cocaine concentrations and thus cocaine's effects, with possible therapeutic benefits. In a collaborative study with the Behavioral Pharmacology Section and the National Institute on Aging Gerontology Research Center, rats pretreated with BChE had a 50% reduction in motor activity response to an IP cocaine challenge compared to rats pretreated with saline. BChE itself had no effect on motor activity. BChE-treated rats had 400-fold increases in plasma and 3-fold increases in cerebrospinal fluid BChE activity 24 hours after treatment, suggesting the possibility of persisting effects from a single enzyme administration. Squirrel monkeys pretreated with BChE before a cocaine challenge show a three-fold decrease in peak plasma cocaine concentrations and a parallel increase in concentrations of the cocaine metabolite ecgonine methylester. BChE added to human plasma in vitro produced a dose-dependent decrease in cocaine half-life, further suggesting the important influence of BChE activity on cocaine pharmacokinetics. Pharmacodynamic approaches being studied include modulation of the brain dopamine reward system with combinations of medications and blockade of relevant neurotransmitter receptors. A recent outpatient open-label clinical trial implemented the former approach using a combination of two dopaminergic medications (bromocriptine, bupropion). The combination was well tolerated by patients, but showed little more efficacy than drug counseling. The second approach is being implemented, in collaboration with the Chemistry & Drug Metabolism Section, by evaluating the effects in humans of an experimental compound, SR141716, which acts as an antagonist at the cannabinoid 1 (CB1, marijuana) receptor in the brain, and on its interaction with smoked marijuana. A single 90 mg dose of SR141716 significantly reduced the psychological (feeling of marijuana intoxication) and cardiovascular (tachycardia, symptomatic hypotension) effects of a marijuana cigarette. SR141716 by itself had no measurable effects, and did not alter THC plasma pharmacokinetics. These findings suggest that CB1 receptors play an important role in mediating the effects of smoked marijuana in humans. Current studies are evaluating the effects of multiple doses of antagonist.